Epidermal CYLD inactivation sensitizes mice to the development of sebaceous and basaloid skin tumors

Abstract

The deubiquitinase-encoding gene Cyld displays a dominant genetic linkage to a wide spectrum of skin-appendage tumors, which could be collectively designated as CYLD mutant–syndrome (CYLDm-syndrome). Despite recent advances, little is understood about the molecular mechanisms responsible for this painful and difficult-to-treat skin disease. Here, we generated a conditional mouse model with epidermis-targeted expression of a catalytically deficient CYLDm through K14-Cre–mediated deletion of exon 9 (hereafter refer to CyldEΔ9/Δ9). CyldEΔ9/Δ9 mice were born alive but developed hair and sebaceous gland abnormalities and dental defects at 100% and 60% penetrance, respectively. Upon topical challenge with DMBA/TPA, these animals primarily developed sebaceous and basaloid tumors resembling human CYLDm-syndrome as opposed to papilloma, which is most commonly induced in WT mice by this treatment. Molecular analysis revealed that TRAF6-K63-Ubiquitination (K63-Ub), c-Myc-K63-Ub, and phospho-c–Myc (S62) were markedly elevated in CyldEΔ9/Δ9 skin. Topical treatment with a pharmacological c-Myc inhibitor induced sebaceous and basal cell apoptosis in CyldEΔ9/Δ9 skin. Consistently, c-Myc activation was readily detected in human cylindroma and sebaceous adenoma. Taken together, our findings demonstrate that CyldEΔ9/Δ9 mice represent a disease-relevant animal model and identify TRAF6 and c-Myc as potential therapeutic targets for CYLDm-syndrome.

CENPV Is a CYLD-Interacting Molecule Regulating Ciliary Acetylated α-Tubulin

“…A strong CENPV expression was also observed in TE, a benign follicular tumor closely related to BCC and considered by some authors as a more differentiated state of the same entity. Interestingly, CYLD inactivation in mice was shown to promote the development of sebaceous and basaloid skin tumors (Jin et al, 2016). Moreover, we report that TEs and CYLs are highly ciliated tumors, similar to BCCs.…”

Clinical, genetic and experimental studies of the Brooke–Spiegler (CYLD) skin tumor syndrome

“…Instead, they need to be challenged with topical administration of chemicals before skin tumors appear, suggesting that Cyld-inactivation itself is not sufficient for tumorigenesis. Interestingly, a recent study indicate that specific inactivation of Cyld in K14-positive hair follicle and basal epidermal cells followed by topical challenge with DMBA and TPA results in development of sebaceous and basaloid tumors with some resemblance to BSSassociated tumors [12]. However, since there are no prior reports of established cell lines or xenografts of tumors from BSS patients, the present PDX model is thus the first preclinical model that truly recapitulates human inherited CYLD-defective cylindromas.…”

“…Previous studies of Cyld-defective mouse models have shown that they do not recapitulate the histological and clinical characteristics of BSS particularly well [11,12]. Thus, these mice do not spontaneously develop skin tumors mimicking cylindromas or spiradenomas.…”

Maternal folic acid depletion during early pregnancy increases sensitivity to squamous tumor formation in the offspring in mice

“…A previous genome-wide geneexpression study revealed that maternal FA deficiency affected the expression level in the offspring of Cyld, which encodes a deubiquitinating enzyme. 11 Cyld was reported to present the genetic attributes of a tumor-suppressor gene, 20 and Cyld regulates keratinocyte differentiation and skin-cancer progression in human and mouse; [24][25][26] notably, in chemical-induced skin-tumor models developed using DMBA/TPA, Cyld-deficient mice were found to be susceptible to papilloma formation due to the acceleration of the NFκB signaling pathway. 25,26 Therefore, we examined Cyld expression at the mRNA and protein levels in the skin and tongue tissues of FA(þ) and FA(−) offspring: At P2, Cyld expression was approximately 38% and 60% lower in the skin of FA(−) offspring than FA(þ) offspring at mRNA and protein level, respectively (Fig.…”

“…23 Especially in the skin, Cyld functions physiologically as a regulator of epidermal differentiation, 24 and its deficiency in the skin accelerates sensitivity to chemically induced skin-tumor development in mice. 25,26 In this study, we examined whether the effects of insufficient maternal FA consumption may induce squamous neoplasia (skin and tongue) in the offspring for the first time and test whether our novel assumption of this being mediated by Cyld is correct or not, using mouse model.…”